MSH2

MSH2 encodes a key protein in the DNA mismatch repair system, essential for detecting and correcting replication errors that threaten genomic stability. 

Germline mutations in MSH2 are strongly associated with Lynch syndrome and related hereditary cancer syndromes, making it a critical biomarker for cancer risk assessment and precision oncology.

What is MSH2?

The MSH2 gene encodes MutS homolog 2, a core protein in the DNA mismatch repair (MMR) system. This system is essential for correcting replication errors, such as base mismatches and insertion-deletion loops, to maintain genomic stability. 

MSH2 functions by forming two main types of protein complexes: MSH2–MSH6 (MutSα), which detects single-base mismatches and short indels (1–2 nucleotides), and MSH2–MSH3 (MutSβ), which recognizes longer indels and branched DNA structures. 

These complexes bind mismatched DNA, recruit other repair proteins like MLH1-PMS2, and initiate a repair process that excises and replaces the incorrect DNA sequence. Without proper MSH2 function, these errors accumulate, increasing the risk for cancer due to genomic instability.

When is MSH2 Testing or Research Relevant?

MSH2 testing may be appropriate in the following scenarios:

Hereditary Cancer Syndromes

Mutations in MSH2 are most clinically relevant in the context of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer, or HNPCC) and related conditions. 

Lynch syndrome is an inherited cancer predisposition syndrome that primarily increases the risk of:

• Colorectal cancer
• Endometrial cancer
• Ovarian, gastric, small intestine, urinary tract, and brain cancers

MSH2 mutations are responsible for approximately 40% of Lynch syndrome cases.

Clinical Testing Scenarios

Genetic testing for MSH2 is recommended in individuals with early-onset colorectal or endometrial cancer, or with a strong family history of Lynch-associated tumors. 

Tumor testing can guide the need for genetic evaluation. Immunohistochemistry (IHC) is often used first to assess protein expression. Loss of nuclear staining for MSH2 and MSH6 suggests an underlying MSH2 mutation. 

Alternatively, microsatellite instability (MSI) testing can detect MMR deficiency at the DNA level. 

These tumor-based tests help identify patients who should undergo targeted germline testing.

MSH2 Genetic Testing: Test Procedure and Interpretation

Testing for MSH2 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for MSH2 genetic testing are considered to be without mutations that can alter the activity of the MSH2 proteins.

What Do MSH2 Mutations Mean?

MSH2 mutations may have the following implications:

Defective MMR and Cancer Risk

Loss-of-function mutations in MSH2 impair the DNA repair process and lead to microsatellite instability—a key feature of Lynch syndrome-associated cancers. 

The cancer risk and age of onset can vary depending on the specific mutation and other modifying factors, including environmental exposures and additional genetic variation.

Clinical Syndromes

The following clinical syndromes have been associated with MSH2 mutations:

Lynch Syndrome (Autosomal Dominant)

In Lynch syndrome, individuals inherit one pathogenic MSH2 variant and one functional copy. A somatic “second hit” that inactivates the remaining normal allele is usually required to trigger tumor development. Lifetime cancer risk is approximately 77% by age 70.

Muir-Torre Syndrome (Variant of Lynch Syndrome)

This subtype of Lynch syndrome includes both internal cancers and uncommon sebaceous skin tumors, such as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas. It is associated with specific MSH2 mutations.

Constitutional Mismatch Repair Deficiency (CMMRD, Autosomal Recessive)

CMMRD results from inheriting pathogenic MSH2 variants on both alleles. It typically presents in early childhood with malignancies such as leukemia, lymphoma, brain tumors, and colorectal cancer. Up to 90% of affected individuals develop cancer by age 18. Skin pigmentation anomalies are also common. 

CMMRD reflects a total loss of MSH2 function across all tissues, leading to widespread repair failure and early-onset disease.

What Does a Negative MSH2 Test Mean?

A negative genetic test for known MSH2 variants does not rule out Lynch syndrome. Other MMR genes, such as MLH1, MSH6, and PMS2, may harbor pathogenic variants. 

If tumor testing shows evidence of mismatch repair deficiency (e.g., MSI-H or IHC loss), further investigation of these additional genes is warranted. The clinical context and family history remain essential in interpreting negative results.

Molecular and Structural Insights

The MSH2 gene is located on chromosome 2p21-p16.3 and encodes a nuclear protein with essential roles in DNA mismatch repair. The protein contains several domains critical for function, including the Walker A ATPase motif and a DNA-binding clamp domain. 

These facilitate conformational changes required for mismatch detection and repair complex recruitment.

MSH2 also plays roles beyond classical MMR. The MSH2–MSH3 complex is involved in double-strand break (DSB) repair by promoting homologous recombination (HR), recruiting and activating EXO1, and cooperating with chromatin remodelers like SMARCAD1. 

Notably, MSH2–MSH3 suppresses error-prone POLθ-mediated end joining (TMEJ), a backup repair pathway that can increase mutational load. 

These additional roles may help explain genomic instability patterns in MSH2-deficient tumors and suggest biomarkers for therapeutic targeting, such as sensitivity to PARP inhibitors.

Variant Interpretation and Clinical Utility

Frameshift and nonsense mutations in MSH2 are generally classified as pathogenic and strongly linked to Lynch syndrome. However, interpreting missense variants remains more challenging. 

Deep mutational scanning studies have shown that only about 11% of MSH2 missense variants cause complete loss of function. Many others, even at conserved sites, may be functionally neutral. 

Functional effect mapping tools now provide stronger evidence for classifying variants of uncertain significance (VUS) and can guide risk stratification, diagnosis, and family counseling.

Clinical Applications

Identifying pathogenic MSH2 variants has broad implications for patient care. It enables diagnosis of Lynch syndrome and related conditions, supports genetic counseling, and prompts cascade testing for at-risk relatives. 

MSH2 mutation carriers benefit from tailored cancer surveillance protocols, including earlier and more frequent colonoscopies and screening for endometrial and other Lynch-associated tumors. 

Genotype-phenotype correlations suggest that MSH2 mutations confer a higher risk of multiple and extra-colonic malignancies compared to MLH1 or MSH6 mutations. Tumor testing (IHC and MSI) remains a valuable tool to guide initial testing and confirm diagnoses.

Aliases

MSH2 is also known by the following names: COCA1, FCC1, HNPCC1, HMSH2, LYNCH1, and MMRCS2.

Conclusion

MSH2 is a central guardian of genomic stability. Germline or somatic loss of MSH2 function significantly increases cancer risk through defective mismatch repair and altered DNA damage responses. 

MSH2 is a high-value biomarker for clinicians in hereditary cancer diagnostics, treatment planning, and family risk assessment. Its emerging roles in double-strand break repair and therapeutic response pathways further highlight its relevance in modern precision oncology.

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